Terminal halo olefins are not only useful synthetic intermediates in organic chemistry, but also valuable target compounds themselves: There is a long-standing history of their use as monomers in polymer science (Marvel et al., J. Am. Chem. Soc. 1939, 61, 3241-3244), but more recently they have also attracted interest in the life sciences (e.g. Kolb et al., J. Med. Chem. 1987, 30, 267-272; Nunnery et al., J. Org. Chem. 2012, 77, 4198-4208; Akiyama et al., Tetrahedron 2013, 69, 6560-6564). In medicinal chemistry, for instance, terminal haloallylamine compounds have been reported to act as inhibitors of amine oxidases (WO 2005/082343, WO 2006/094201, WO 2007/120528, WO 2013/163675).
Terminal halo olefins are synthetically accessible by a limited number of approaches (van Steenis et al., J. Chem. Soc., Perkin Trans. 1, 2002, 2117-2133; Landelle et al., Chem. Soc. Rev. 2011, 40, 2867-2908; Koh et al., Nature 2016, 531, 459-465, Nguyen et al., Science 2016, 352, 569), e.g. by elimination, addition, electrophilic or nucleophilic halogenation, olefination (e.g. Wittig-type) reactions or cross-metathesis. However, the preparation of terminal halo olefins in high stereoselectivities is often one of the major challenges.
The recent approaches for the terminal halo olefin formation within the context of amine oxidase inhibitor synthesis comprise a Wittig reaction, starting from ketones, followed by separation of the E/Z isomers via chromatographic techniques or recrystallization (WO 2005/082343, WO 2007/120528, WO 2013/163675). In addition, a halogenation-dehydrohalogenation of olefins as well as the base-induced decarboxylative halogen elimination of halomethyl-substituted malonester derivatives have been disclosed (McDonald et al., J. Med. Chem. 1985, 28, 186-193; McDonald et al., Tetrahedron Letters 1985, 26, 3807-3810; WO 2005/082343, WO 2006/094201).
One further approach for the formation of terminal halo olefins is the protodecarboxylation of α-halo-acrylic acid derivatives, which are accessible, e.g. by the Horner-Wadsworth-Emmons reaction starting from carbonyl species. However, the scope of this protodecarboxylation used to be limited to particular substrates, such as perfluorated acrylic acids or acrylic acids with unsaturated β-substituents: Sodium(I), silver(I) and copper(II) salts of perfluorated acrylic acid derivatives were reported to undergo protodecarboxylation upon substantial heating (Cherstkov et al., Izvestiya Akademii nauk SSSR, Seriya Khimicheskaya 1986, 1, 119-122; Cherstkov et al., Izvestiya Akademii nauk SSSR, Seriya Khimicheskaya 1989, 6, 1336-1340). Likewise, protodecarboxylation of mucohalic acids ((Z)-2-3-dihalo-4-oxo-2-butenoic acids, i.e. bearing a carbonyl substituent in β-position) to afford (Z)-α,β-dihaloacrolein can be effected by excessive heating (Duczek et al., Synthesis 1992, 10, 935-936). Acrylic acid derivatives with β-pyrimidinyl-substituents may be subject to protodecarboxylation by acidification at elevated temperatures (DD 259803). Acrylic acids with β-phenyl-substituents (i.e. cinnamic acid derivatives) can be decarboxylated by employment of copper(0)/copper(II)/quinoline and heating to above 200° C. (Elkik, Bull. Soc. Chim. Fr. 1967, 5, 1569-71), by using excessive copper(II) in the presence of molecular sieve in DMAC/DMSO at 140° C. (Rousée et al., Chem. Eur. J. 2014, 20, 15000-15004) or by cofactor catalysis (Payne et al., Nature 2015, 522, 497-501).
In contrast, no single application of a protodecarboxylation step of acrylic acid derivatives with two vicinal saturated carbon substituents has been reported. In addition to the limited substrate scope, the use of stoichiometric amounts of metals and the heating to high temperatures constitute further drawbacks of the conversions reported to date, which have prevented a more widespread application of this reaction.